5,13-dialkylgon-3-one compounds



United States Patent 3,474,116 5,13-DIALKYLGON-3-ONE COMPOUNDS George C. Buzby, Jr., Philadelphia, and Herchel Smith,

Wayne, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Apr. 4, 1967, Ser. No. 628,270 Int. Cl. C07c 169/10, 167/14; A61k 27/00 US. Cl. 260-397.4 10 Claims ABSTRACT OF THE DISCLOSURE The compounds of the class of 5,13-dialkylgon-3-one compounds useful as anti-androgenic agents.

BACKGROUND OF THE INVENTION This invention relates to the field of new physiologically active 5,13-dialkylgonan-3-one, 1,5,13-trialkylgonan- 3-one and 2-halo-5,l3-dialkylgonan-3-one compounds, novel process for their preparation and new intermediates useful in the preparation thereof.

SUMMARY OF THE INVENTION More particularly, this invention is directed to compounds of the formulae:

OR H active substances which are useful as anti-androgenic agents. Hence, they may be administered in lieu of known anti-androgenic agents such as A-norprogesterone.

The compounds may be formulated for such administration based on the activity of the particular compound and the requirements of the patient.

DESCRIPTION OF THE PREFERRED- EMBODIMENTS The compounds of this invention may be prepared according to the process of this invention which may be represented by the following reaction scheme wherein R, R R and R are as hereinbefore defined, and X is halo; and R is alkyl:

ice

III IV According to one feature of this invention, 5,13-dialkylgon-3-one compounds of the Formula I are treated with halogen, preferably, bromine or chlorine, in an inert organic solvent to yield the 2-halo-5,l3-dialkylgon-3-one compounds of Formula II.

The initial 5,13-dialkylgon-3-one compounds (I) may be prepared in accordance with any prior art processes such as described by G. C. Buzby et al. in copending application Ser. No. 536,294, filed Mar. 22, 1966.

The 2-halo-5,13-dialkylgon-3-one compounds (II) are then refluxed with lithium salt, preferably, lithium carbonate and lithium chloride in an inert organic solvent, to yield the corresponding 5,l3-dia1kylgon-1-en-3-ones (III), which are some of the pharmacologically active final products of this invention.

In accordance with another feature of this invention, the 5,1B-dialkylgon-l-en-B-ones are treated with an organo-metal compound, such as Grignard compound, to yield the 1,5,13-trialkylgon-3-one compounds of Formula IV, which are additional pharmacologically active final products of this invention.

Additionally, the 3,17-dione compounds of this invention may be prepared by treating the compounds of Formula IV, wherein R and R are hydrogen, with an oxidizing agent, such as Jones reagent.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 13,8,17a-diethyl-2-bromo-17B-hydroxy-5- methylgonan-3-one AEE; 3.0, 5.80, 5.86 Analysis.Calcd. for C H O Br requires: Br, 18.0%. Found: Br, 16.9%.

EXAMPLE 2 13,17-diethyl-2-bromo-17,8-hydroxy-5-methylgonan- 3-one, l7-acetate Following the procedure of Example 1, but substituting 13,17 diethyl 17B hydroxy-5-methylgonan-3-one, l7- acetate for l3,17-diethyl-17 3-hydroxy-5-methylgonan-3- one there is obtained 13,17 diethyl 2 bromo-17fl-hydroxy-5-methylgonan-3-one, 17-acetate.

EXAMPLE 3 l3,17-diethyl-2-bromo-1718-hydroxy-5-ethylgonan6-one Following the procedure of Example 1, but substituting 13,l7-diethyl-17fi-hydroxy-5-ethylgonan-3-one for 13,17- diethyl 17B -hydroxy-5-methylgonan-3-one, there is obtained 13,17 diethyl-2-bromo-17,8-hydroxy-5-ethylgonan- 3-one.

3 EXAMPLE 4 13,17-diethyl-2-bromo-17/3-hydr0xy-5- propylgonan-3-one Following the procedure of Example 1, but substituting 13,17 diethyl 17p hydroxy-5-propylgonan-3-one for 13,17-diethyl-17B-hydroxy-5-methylgonan-3-one, there is obtained 13,17 diethyl 2 bromo-l7fl-hydroxy-5-propylgonan-3-one.

EXAMPLE 5 13,17-diethyl-2-bromo-17,8-hydroxy-5-butylgonan-3-one Following the procedure of Example 1, but substituting 13,17-diethyl-17fl-hydroxy-5-butylgonan-3-one for 13,17- diethyl-17fl-hydroxy-5-methylgonan-3-one, there is obtained 13,17-diethy1-2-bromo-17fi-hydroxy-5-butylgonan- 3-one.

EXAMPLE 6 13-ethyl-17-methyl-2-bromo-NIB-hydroxy- 5-methylgonan-3one Following the procedure of Example 1, but substituting 13 ethyl-17-methyl-17p-hydroxy-5-methylgonan-3-one for 13,17-diethyl-17fl-hydroxy-5-methylgonan-3-one there is obtained 13-ethyl-17-methyl-2-bromo-17 3-hydroxy-5- methylgonan-3-one.

EXAMPLE 7 13-ethyl-17-propyl-2-bromo-17,3-hydroxy-5- methylgonan-3-one Following the procedure of Example 1, but substituting 13-ethyl-17-propyl-17B-hydroxy-5-methylgonan-3-one for 13,17-diethyl-17l3-hydroxy-5-methylgonan-3one there is obtained 13 ethyl 17-propyl-2-bromo-17p-hydroxy-5- methylgonan-3-one.

EXAMPLE 8 13-ethyl-17-butyl-2-bromo-17,8-hydroxy-5- methylgonamS-one Following the procedure of Example 1, but substituting 13 ethyl 17 butyl 17fl-hydroxy 5-methylgonan-3-one for 13,17 diethyl 17,8 hydroxy-5-methylgonan-3-one, there is obtained 13 ethyl l7-butyl-2-bromo-l7 3-hydroxy-S-methylgonan-3-one.

EXAMPLE 9 13-propyl-17-methyl-2-bromo-17 8-hydroxy-5- methylgonan-3-one Following the procedure of Example 1, but substituting 13 propyl-l7-methyl-17fl-hydroxy-5-methylgonan-3-one for 13,17 diethyl 17fi-hydroxy-5-methylgonan-3-one, there is obtained 13-propyl-17-methyl-2-bromo-17fi-hydroxy-5-methylgonan-3-one.

EXAMPLE l 13-butyl-17-methyl-2-bromo-17,8-hydroxy-5- methylgonan-3-one -methyl-2-bromo-19-norandrostan-17-ol-3-one Following the procedure of Example 1, but substituting S-methyl-19-norandrostan-17-ol-3-one for 13,17-diethyl- 17 hydroxy 5 methylgonan-3-one there is obtained 5- methyl-Z-bromo-19-norandrostan-l7-ol-3-one.

EXAMPLE 1 2 13-ethyl-2-bromo-17;3-hydr-oxy-S-methylgonan-B-one Following the procedure of Example 1, but substituting 13 ethyl 17 3-hydroxy-5-methylgonan-3-one for 13,17- diethyl 17 hydroxy-5-methylgonan-3-one, there is obtained 13 ethyl-2-bromo-17fi-hydroxy-5-methylgonan- 3-one.

EXAMPLE 13 13,l7-diethyl-17B-hydroxy-5-methylgon-l-en-3-one A mixture of 2.25 gm. of 13,17-diethyl-2-bromo-17B- hydroxy-5-methylgonan-3-one, 0.71 gm. of lithium carbonate and 0.41 gm. of lithium chloride in 40 ml. of dimethylformamide is refluxed under nitrogen for 4 hours. The reaction mixture is then cooled, filtered, the cake washed with ether and the filtrate is poured into water. The ether layer is then separated, washed, dried and the solvent removed to yield 0.915 gm. of a solid.

The solid is chromatographed over neutral alumina to yield 0.720 gm. of 13,17-diethyl-17fl-hydroxy-5-methylgon-l-en-3-one, M.P. 124-127",

A551 2.91, 5.99; A523, 237 m (e 8,600)

Analysis.Calcd. for C H O requires: C, 79.95; H, 10.37. Found: C, 79.46; H, 10.20.

Treatment of the products of Examples 2 through 12 according to the procedure of Example 13 yields, respectively, the products of the following Examples 14 through 24:

13,17-diethyl-15,5g-dimethyl-17B-hydroxygonan-3-one 0.703 gm. of 13,17-diethyl-17B-hydroxy-5-methylgon- 1-en-3-one in 10 ml. of dry tetrahydrofuran is added dropwise to 40 ml. of dry tetrahydrofuran containing cuprous chloride (1.0 g.) and 20 ml. of methyl magnesium bromide 3 M in ether (20 ml.). The reaction is stirred an hour, poured into brine saturated with HC1 and the ether layer washed, dried and evaporated in vacuo. The residue is recrystallized from ether to yield 0.380 g. of 13,17 diethyl 1,5 dimethyl-17fl-hydroxygonan-3-one, M.P. 154156;

Analysis.Calcd. for C H O requires: C, 79.71; H, 11.05. Found: C, 79.30; H, 11.00.

Similarly, by following the procedure of Example 25, but substituting another Gn'gnard reagent for the methyl magnesium bromide, such as ethyl magnesium bromide, propyl magnesium bromide, butyl magnesium bromide, and the like, the corresponding l-alkyl derivative is obtained.

EXAMPLE 26 13,17-diethyl-1,S-dimethyl-17B-hydroxygonan-3-one 17-acetate Following the procedure of Example 25, but substituting 13,17-diethyl-17 8-hydroxy-5-methylgon 1 en-3- one, 17-acetate for 13, 17-diethyl-17fl-hydroxy-5-methylgon-1-en-3-one, there is obtained 13,17-diethyl-l,5-dimethyl-17fi-hydroxygonan-3-one, 17-acetate.

EXAMPLE 27 5,13,17 triethyl-1-methyl-l7B-hydroxyonan-3-one Following the procedure of Example 25, but substituting 5,13,17-triethyl-17/3-hydroxygon l en-3-one for 13,17-diethtyl-17fi-hydroxy-5-methylgon 1 en-3-one there is obtained 5,13,17-triethyl-1-methyl7l7fi-hydroxygonan-S-one.

EXAMPLE 28 13,17-diethyl-l-methyl-5-propy1-17/3-hydroxygonan-3- one 13,17 -diethy1-1-methyl-5 -butyl-17B-hydroxygonan-3-one Following the procedure of Example 25, but substituting l3,17-diethyl-l7p-hydroxy-5-butylgon-1-en-3-one for 13,17-diethyl-17/8 hydr-oxy-5-propylgon-1-en-3-one there is obtained 13,17-diethyl 1 methyl-5-butyl-17,6-hydroxygonan-3-one.

EXAMPLE 30 Following the procedure of Example 25, but substituting 13-ethyl-17-methyl-17 8-hydroxy-5-methylgon-1-en-3- one for 13,17-diethyl-17B-hydroxy-5-methylgon-1-en-3- one there is obtained 13-ethyl-17-pr0pyl-1,5-dimethyl-17B- hydroxygonan-3-one.

EXAMPLE 31 13-ethyl-17-propyl-1,S-dimethyl-17B-hydroxygonan- 3-one Following the procedure of Example 25, but substituting 13 ethyl-17-propyl-l7fl-hydroxy-5-methylgon-1-en-3- one for l3,l7-diethyl-l7fl-hydroxy 5 methylgon-l-en-3- one there is obtained l3-ethyl-17-propyl-1,5-dirnethyl-l7flhydroxygonan-3-one.

EXAMPLE 32 1 3-ethyl- 1 7-butyl- 1,5 -dimethyl- 17 p-hydroxygon an-3 3-one Following the procedure of Example 25, but substituting 13-ethyl-17-butyl-17B-hydroxy-5-methylgon-l-en-3-one for 13,17 diethyl-17/8-hydroxy-5-methylgon-1-en-3-one, there is obtained 13-ethyl-l7-butyl-1,5-dimethyl-17B-hydroxygonan-3-one.

EXAMPLE 33 13-propyl-17-methyl-1,S-dimethyl-17B-hydroxygonan- 3-one Following the procedure of Example 25, but substituting l3-propyl-17-methyl-17B-hydroxy-5-methy1gon-l-en- 3-one for 13,17-diethy1-17 3-hydr0xy-5-methy1gon-1-en-3- one there is obtained l3-propyl-17-methyl-1,5-dimethyl- 17B-hydroxygonan-3-one.

EXAMPLE 34 13-butyl-l7-methy1-1,5-dimethyl-17fl-hydroxygonan- 3-one Following the procedure of Example 25, but substituting 13-butyl-17-methyl-17B-hydroxy-5-methylgon-l-en-3- one for 13,17-diethyl-17fi-hydroxy-5-methylgon-l-en-3- one, there is obtained 13-butyl-17-methyl-1,5-dimethyl- 17/8-hydroxygonan-3-one.

EXAMPLE 35 1,S-dimethyl-19-norandrostan-17-ol-3-one Following the procedure of Example 25, but substituting S-met-hyl l9 norandrost-l-en-17-ol-3-one for 13,17-

6 diethyl-l7fi-hydroxy-5-methylgon-1-en-3-one there is obtained 1,i-dimethyl-l9-norand rostan-17-ol-3-one.

EXAMPLE 36 13-ethyl-1,5-dimethylgonane-3,l7-dione invention.

What is claimed is: 1. A compound selected from those of the formulae and wherein R and R are each alkyl groups of less than 5 carbon atoms; R is selected from the group consisting of hydrogen and lower acyl; R is selected from the group consisting of hydrogen and alkyl of less than 5 carbon atoms; R" is selected from the group consisting of hydrogen and alkyl of less than 5 carbon atoms; and X is selected from the group consisting of hydrogen, bromine and chlorine with the proviso that R is an alkyl of 1 to 4 carbon atoms when X is hydrogen.

2. A compound according to claim 1 having the structural formula R Lam R W Ai wherein R, R R and R are as hereinbefore defined.

7 8 6. A compound according to claim 5 that is 13,17- 9. A compound according to claim 7 in which R is diethyl-Z-bromo-17fl-hydroxy-S-methylgonan-3-one. ethyl and R, R R and R are as hereinbefore defined.

7. A compound according to claim 1 having the struc- 10. A compound according to claim 7 in which R tural formula is ethyl and R, R R and R are as hereinbefore defined.

References Cited R if? UNITED STATES PATENTS i 1 3,083,196 3/1963 Fried et al 260-2395 3 I 10 OTHER REFERENCES Mori: Chem. & Pharm. Bull., vol. 10, May 1962, pp.

382-6. Ginsig et al.: J. Am. Chem. Soc., 87, 20, Oct. 20, 1965,

wherein R, R R and R are as hereinbefore defined, and ELBERT L. ROBERTS, Primary Examiner R is an alkyl of 1 to 4 carbon atoms.

-8. A compound according to claim 7 that is 13,17- S. Cl. X-R. diethyl-1,5-dimethyl-175-hydroxygonan-3-one. 260999 

